Mutations causing late-onset neurodegenerative diseases often remain phenotypically latent for decades before the first symptoms of neurodegeneration are detected. The subtle effects of the mutations on neuronal function, combined with cell-line-to-cell line variability makes modeling diseases like ALS extremely challenging. To increase the robustness of in vitro ALS models, we will generate a set of 20-60 cell lines derived from an ALS iPSC line carrying a highly penetrant and aggressive FUSP525L mutation. In half of these cell lines we will correct the disease-causing mutation using a CRISPR-mediated homologous recombination strategy. Additionally, we will introduce a unique genomic barcode into each of the isogenic cell lines. These barcodes will be used to distinguished between corrected and ALS cells, and will also be used as a means of motor neuron quantification through barcode sequencing. We will use this system to examine whether FUS mutant ALS motor neurons exhibit basal decreases in their fitness, and whether stressors that mirror known ALS phenotypes by inducing ER stress, misfolded protein accumulation, or mitochondrial dysfunction can selectively potentiate the degeneration of ALS motor neurons over their isogenic wild-type counterparts. The proposed platform could then easily be adapted to screen full libraries of bioactive compounds for additional stressors that might illuminate novel degenerative pathways or point to new therapeutic targets. Finally, this platform will be invaluable for the discovery of new compounds that decrease ALS motor neuron degeneration in response to stressors, and may contribute to the discovery of new therapeutic agents for a disease where there are currently very few options for treatment.